Efficacy and safety of topiramate for the treatment of chronic migraine: A randomized, double-blind, placebo-controlled trial

Stephen D. Silberstein, Richard B. Lipton, David William Dodick, Frederick G. Freitag, Nabih Ramadan, Ninan Mathew, Jan L. Brandes, Marcelo Bigal, Joel Saper, Steven Ascher, Donna M. Jordan, Steven J. Greenberg, Joseph Hulihan

Research output: Contribution to journalArticle

324 Citations (Scopus)

Abstract

Objective. - To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. Methods. - This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. Results. - The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P =.010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P =.032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. Conclusions. - Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

Original languageEnglish (US)
Pages (from-to)170-180
Number of pages11
JournalHeadache
Volume47
Issue number2
DOIs
StatePublished - Feb 2007

Fingerprint

Migraine Disorders
Placebos
Safety
Therapeutics
topiramate
Respiratory Tract Infections
Fatigue
Headache
Maximum Tolerated Dose
Paresthesia
Neurologic Examination
Nausea
Multicenter Studies
Physical Examination

Keywords

  • Chronic daily headache
  • Clinical trial
  • Migraine
  • Preventive treatment
  • Topiramate
  • Transformed migraine

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Efficacy and safety of topiramate for the treatment of chronic migraine : A randomized, double-blind, placebo-controlled trial. / Silberstein, Stephen D.; Lipton, Richard B.; Dodick, David William; Freitag, Frederick G.; Ramadan, Nabih; Mathew, Ninan; Brandes, Jan L.; Bigal, Marcelo; Saper, Joel; Ascher, Steven; Jordan, Donna M.; Greenberg, Steven J.; Hulihan, Joseph.

In: Headache, Vol. 47, No. 2, 02.2007, p. 170-180.

Research output: Contribution to journalArticle

Silberstein, SD, Lipton, RB, Dodick, DW, Freitag, FG, Ramadan, N, Mathew, N, Brandes, JL, Bigal, M, Saper, J, Ascher, S, Jordan, DM, Greenberg, SJ & Hulihan, J 2007, 'Efficacy and safety of topiramate for the treatment of chronic migraine: A randomized, double-blind, placebo-controlled trial', Headache, vol. 47, no. 2, pp. 170-180. https://doi.org/10.1111/j.1526-4610.2006.00684.x
Silberstein, Stephen D. ; Lipton, Richard B. ; Dodick, David William ; Freitag, Frederick G. ; Ramadan, Nabih ; Mathew, Ninan ; Brandes, Jan L. ; Bigal, Marcelo ; Saper, Joel ; Ascher, Steven ; Jordan, Donna M. ; Greenberg, Steven J. ; Hulihan, Joseph. / Efficacy and safety of topiramate for the treatment of chronic migraine : A randomized, double-blind, placebo-controlled trial. In: Headache. 2007 ; Vol. 47, No. 2. pp. 170-180.
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abstract = "Objective. - To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. Methods. - This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. Results. - The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8{\%} of the topiramate group and 55.2{\%} on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P =.010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P =.032). Treatment-emergent adverse events occurred in 132 (82.5{\%}) and 113 (70.2{\%}) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8{\%}), upper respiratory tract infection (n = 22, 13.8{\%}), and fatigue (n = 19, 11.9{\%}). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4{\%}), fatigue (n = 16, 9.9{\%}), and nausea (n = 13, 8.1{\%}). Discontinuations due to adverse events occurred in 18 (10.9{\%}) topiramate subjects and 10 (6.1{\%}) placebo subjects. There were no serious adverse events or deaths. Conclusions. - Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.",
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TY - JOUR

T1 - Efficacy and safety of topiramate for the treatment of chronic migraine

T2 - A randomized, double-blind, placebo-controlled trial

AU - Silberstein, Stephen D.

AU - Lipton, Richard B.

AU - Dodick, David William

AU - Freitag, Frederick G.

AU - Ramadan, Nabih

AU - Mathew, Ninan

AU - Brandes, Jan L.

AU - Bigal, Marcelo

AU - Saper, Joel

AU - Ascher, Steven

AU - Jordan, Donna M.

AU - Greenberg, Steven J.

AU - Hulihan, Joseph

PY - 2007/2

Y1 - 2007/2

N2 - Objective. - To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. Methods. - This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. Results. - The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P =.010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P =.032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. Conclusions. - Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

AB - Objective. - To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. Methods. - This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. Results. - The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P =.010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P =.032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. Conclusions. - Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

KW - Chronic daily headache

KW - Clinical trial

KW - Migraine

KW - Preventive treatment

KW - Topiramate

KW - Transformed migraine

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